The Phase 2 CENTAUR trial testing AMX0035 for amyotrophic lateral sclerosis (ALS) was designed to include patients with the most severe disease to yield the most powerful results possible, a researcher explained in a recent webinar hosted by Amylyx Pharmaceuticals, which is developing the therapy.
During the webinar, experts discussed how AMX0035 was developed and the strategy used in the CENTAUR trial to test the investigational therapy.
AMX0035 is a combination therapy that includes two small molecules — tauroursodeoxycholic acid and sodium phenylbutyrate — both of which act to prevent neural cell death by targeting the mitochondria (which provide the cell with energy among other functions) and the endoplasmic reticulum (which is involved in making proteins).
According to Justin Klee, co-founder and president of Amylyx, this therapeutic strategy is somewhat unique in that it doesn’t try to prevent the root cause of ALS, the process of which, in most cases, has been occurring for a long time before a person is diagnosed; rather, it aims to preserve motor neurons.
“What ultimately causes clinical decline in ALS is that motor neurons in the brain and spine degenerate and die,” Klee said. “What we thought was, if we could identify or develop a therapy that could intervene at the level of cell death and degeneration, then perhaps we could have a therapy that would work for ALS, as well as neurodegeneration as a whole.”
Preclinical data have lent credence to this idea – but only trials in humans can reliably indicate whether a potential therapy actually helps. That’s where the CENTAUR trial — which is being funded by Amylyx as well as nonprofits — comes in.
In the trial, 132 people with a diagnosis of either sporadic or familial ALS were randomized 2:1 to treatment with either AMX0035 or a placebo for 24 weeks (about six months). Essentially, for every three patients included in the trial, two would receive the active ingredient and one would be given a placebo.
Participants are given the option after the trial to enroll in an open-label extension study (in which they know they are receiving the active treatment); so far, about 90% of participants have opted into this extension, and the longest follow-up time for which there is currently data is one and a half years.
Sabrina Paganoni, MD, PhD, a professor at Harvard who is leading the trial, explained that CENTAUR was designed to maximize the data that could be obtained using the fewest participants and in the least amount of time. This involved using stringent enrollment criteria — in essence, only people who were predicted to have the most severe ALS with the fastest disease progression were enrolled.
“This design afforded us the highest statistical power,” Paganoni said. “In other words, when testing the drug in the most severe patients — the ones who need the treatment the most — if we can stop or slow down the disease in these patients, we expect to do the same in all patients.”
Paganoni added that, if AMX0035 reaches the point of being approved by regulatory agencies for ALS treatment, it is expected to be approved for all patients with ALS.
The trial’s main goal is to assess changes in the ALS Functional Rating Scale-Revised, “a questionnaire where we ask patients how they are doing in terms of their speech, swallowing, ability to walk, ability to dress themselves,” Paganoni said.
Secondary objectives include muscle strength, respiratory function, and biomarkers of ALS, including the neurofilament marker of neurodegeneration.
Researchers are also following patients for survival, but because patients in CENTAUR were enrolled early in their disease course — within eight months after symptom onset — few deaths occurred during CENTAUR’s six-month follow-up. Researchers are hoping to gather more data during the extension trial.
“In the context of the open-label extension, we are following people long term, and we will be able to provide data with respect to survival,” Paganoni said. “We will be following patients for as long as 18 months after the completion of CENTAUR.”
However, Paganoni adds that survival is no longer required for registration of a new agent; the field is evolving to more functional measures, which help monitor meaningful functional changes in shorter periods of time.
Both Klee and Paganoni acknowledge that AMX0035 isn’t likely to be a “cure” for ALS, but, Klee said, it may be a “meaningful first spark” in turning ALS from a rapidly progressing condition into one that can be managed chronically.